200 Years of The Haloform Reaction: Methods and Applications

Abstract

Discovered in 1822, the haloform reaction is one of the oldest synthetic organic reactions. The haloform reaction enables the synthesis of carboxylic acids, esters or amides from methyl ketones. The reaction proceeds via exhaustive α-halogenation and then substitution by a nucleophile to liberate a haloform. The methyl group therefore behaves as a masked leaving group. The reaction methodology has undergone several important developments in the last 200 years, transitioning from a diagnostic test of methyl ketones to a synthetically useful tool for accessing complex esters and amides. The success of the general approach has been exhibited through the use of the reaction in the synthesis of many different complex molecules in fields ranging from natural product synthesis, pharmaceuticals, agrochemicals, fragrants and flavourings. The reaction has not been extensively reviewed since 1934. Therefore, herein we provide details of the history and mechanism of the haloform reaction, as well as an overview of the developments in the methodology and a survey of examples, particularly in natural product synthesis, in which the haloform reaction has been used.

Keywords: Carboxylic acid; Ester; Haloform; Halogenation; Oxidation.

Figure 1

The haloform reaction can be used to transform methyl ketones to carboxylic acids, esters and amides.

Figure 2

Non methyl ketone substrate classes susceptible to the haloform reaction. Ar=Aryl.

Figure 3

Serullas’ serendipitous discovery of the haloform reaction.

Figure 4

Haloform degradation contributed to the structural determination of α‐pinene, among other terpenes.

Figure 5

Mechanism of the haloform reaction. RLS=Rate limiting step.

Figure 6

Modelled equilibrium constants for the individual steps in the haloform reaction of 4‐fluoroacetophenone (Ar=4‐F‐C₆H₄) with primary and secondary alcohols.

Figure 7

Non classical haloform reaction with iodine and pyridine.

Figure 8

Haloform reaction of higher alkyl (i. e. non methyl) ketones (nd=not detected).

Figure 9

Haloform reaction of cycloalkanones.

Figure 10

The use of a phase‐transfer catalyst enables a double haloform reaction to produce diacids.

Figure 11

Haloform reaction under inverse phase transfer catalysis conditions with cyclodextrins.

Figure 12

Haloform reaction with sodium bromite.

Figure 13

Haloform reaction with BTMABr₃ as a substitute for bromine.

Figure 14

Haloform reaction with a combination of lithium hypochlorite and sodium hypochlorite.

Figure 15

Haloform reaction under non‐aqueous conditions using a reagent quantity of water.

Figure 16

Formation of a carboxylic acid in the presence of an ester.

Figure 17

Discovery that esters can be synthesised via the haloform reaction with alcohol cosolvents..

Figure 18

Synthesis of simple alkyl esters via a haloform reaction with iodine and pyridine.

Figure 19

Idealised mechanism for electrochemical haloform synthesis of esters.

Figure 20

Methyl ester synthesis via electrochemical haloform reaction.

Figure 21

Synthesis of methyl and ethyl esters via electrochemical haloform reaction.

Figure 22

Haloform reaction with stoichiometric alcohols. Bn=Benzyl.

Figure 23

Synthesis of ethyl and propyl esters via haloform reaction with xanthate reagents.

Figure 24

General “haloform coupling” reaction, with selected examples involving both primary and secondary alcohols.

Figure 25

Primary amide synthesis via haloform reaction with aqueous ammonia.

Figure 26

Primary amide synthesis using aqueous ammonia and THF.

Figure 27

Secondary and tertiary amide synthesis via haloform reaction with stoichiometric amines.

Figure 28

Primary amide synthesis via haloform reaction with stoichiometric aqueous ammonia and additional base.

Figure 29

Primary amide synthesis via a haloform reaction with stoichiometric azide as used as the source of nitrogen.

Figure 30

Amide synthesis via electrochemical haloform reaction with formamides.

Figure 31

Proposed radical pathway for haloform reaction with sub‐stoichiometric iodine and TBHP.

Figure 32

Two proposed mechanisms for the reaction with CuI and KI. Bn=Benzyl.

Figure 33

Amide synthesis via electrochemical haloform reaction with amines. Bn=Benzyl.

Figure 34

Haloform‐type aromatic amination. Het=Heterocycle.

Figure 35

The haloform reaction used in the formation of 2‐arylpropanoic acids (31, 32).

Figure 36

Synthesis of ¹³C₁₂‐benzoyl‐peroxide (33) via the haloform reaction.

Figure 37

A haloform reaction and reductive decarbonylation yields an alcohol (35) from a methyl ketone (34).

Figure 38

Production of the commodity chemical succinic acid (13) from lignocellulosic biomass (37).

Figure 39

Proposed improvement to the synthetic route to fluticasone propionate (41).

Figure 40

Mykhailiuk's scale‐up of Michls two‐step process to bicyclopentane diacid 43, with the haloform reaction as the second step.

Figure 41

Total 13‐step synthesis of smenospondiol (48).

Figure 42

Total synthesis of (±)‐9‐isocyanopupukeanane (54).

Figure 43

Total synthesis of anthoplalone 60, synthesised by Ihara and coworkers in 1994.

Figure 44

Total synthesis of heliolactone (63).

Figure 45

Total synthesis of (±)‐methyl epi‐jasmonate (69).

Figure 46

Synthesis of veratric acid (72).

Figure 47

Total synthesis of Silphilperfol‐5‐ene (76).

Figure 48

Total synthesis of (+)‐(S,S)‐(cis‐6‐methyltetrahydropyran‐2‐yl)acetic acid (81).

Figure 49

Luzopeptin A−C structures (82–84). Quinaldic acid derived groups in red.

Figure 50

Total synthesis of quinaldic acid (88), a major component of the complex luzopeptin natural products.

Figure 51

Total synthesis of balanol (94).

Figure 52

Total synthesis of umbrosone (100).

Figure 53

Total synthesis of (+)‐upial (105).

Figure 54

Total synthesis of Platensimycin (110).

Figure 55

Total synthesis of caulersin (116).